Integrated drug-in-cell therapy of in-stent restenosis

支架内再狭窄的综合药物细胞治疗

• 批准号: 9256528
• 负责人: Michael Chorny
• 金额: $ 25.2万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256528
• 关键词: Acute; Address; Adverse effects; Affect; Angioplasty; Animals; Arterial Injury; Arteries; Atherosclerosis; Benzoates; Biological Assay; Blood Vessels; Carotid Atherosclerotic Disease; Carotid stent; Cell Therapy; Cells; Chronic; Clinical; Clinical Trials; Coculture Techniques; Control Animal; Development; Disease; Dose; Drug Targeting; Drug or chemical Tissue Distribution; Effectiveness; Encapsulated; Endothelial Cells; Endothelium; Estradiol; Estradiol Benzoate; Estrogens; Evaluation; Event; Exhibits; Functional disorder; Generalized Atherosclerosis; Genes; Growth; Iatrogenesis; Image Analysis; Incidence; Injury; Intervention; Kinetics; Lesion; Life; Magnetic nanoparticles; Magnetism; Mechanics; Mediating; Metals; Methods; Modality; Modeling; Modification; Molecular; NOS3 gene; Natural regeneration; Nitric Oxide; Nitric Oxide Synthase; Obstruction; Outcome; Pathway interactions; Patient risk; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Procedures; Process; Production; Property; Rattus; Recovery; Reporting; Safety; Smooth Muscle Myocytes; Source; Stenosis; Stents; Techniques; Treatment Efficacy; Vascular Diseases; antiproliferative agents; base; bioluminescence imaging; cardiovascular risk factor; cell injury; computerized; effective therapy; efficacy study; experimental study; gene therapy; healing; human disease; implantation; magnetite ferrosoferric oxide; morphometry; nanocarrier; nanoparticle; novel; novel therapeutics; particle; poly(lactide); prevent; protective effect; public health relevance; repaired; restenosis; targeted delivery; uptake; vector

 DESCRIPTION (provided by applicant): Injury-triggered renarrowing (restenosis) of arteries treated with angioplasty to relieve atherosclerotic obstruction remains a challenge due to a lack of therapies combining adequate efficacy and safety. Strategies aimed at accelerated vascular healing and endothelium regeneration have potential to prevent restenosis while avoiding the side effects of the currently used therapies. However, in order to realize this potential a significant improvement in their efficiency is required. This proposal is concerned with an integrated drug-in-cell antirestenotic strategy based on dual functionalization of endothelial cell with drug-loaded magnetic nanocarriers to provide them with capacity for stent-targeted delivery and enhanced antirestenotic effectiveness. The latter is achieved by inducing and activating endothelial nitric oxide synthase with estradiol formulated in magnetic nanoparticles (MNP) in the form of its precursor, estradiol benzoate (E2Bz). The present studies will establish feasibilit of using this approach for preventing in-stent restenosis and achieving facilitated reendothelialization in a validated rat model of atherosclerosis reproducing key features of human disease .The following specific aims will be addressed: AIM 1: Drug-in-cell approach evaluation and optimization in culture and co-culture studies. E2Bz-loaded biodegradable MNP will be formulated, and their size, composition, magnetic properties and drug release profile will be characterized. Cell compatibility, internalization and degradation kinetics of MNP, as well as E2Bz-induced nitric oxide synthesis by MNP-functionalized endothelial cells and its growth inhibitory effect on co-cultured smooth muscle cells will be the main endpoints of the Aim 1 experiments. AIM 2: Targeting, reendothelialization and efficacy studies. Arterial localization, tissue distribution and endothelium recovery after magnetically targeted delivery of functionalized cells will be studied in the rat atherosclerosis/ carotid stenting model. The extent of restenosis will be determined two weeks post-delivery by computerized morphometry, and the pharmacological effect of cell functionalization will be delineated using animals treated with cells loaded with blank MNP as controls.

 描述（由申请人提供）：由于缺乏结合足够功效和安全性的治疗策略，通过血管成形术缓解动脉粥样硬化阻塞的损伤触发的动脉再狭窄（再狭窄）仍然是一个挑战。旨在加速血管愈合和内皮再生的策略有潜力。预防再狭窄，同时避免目前使用的疗法的副作用。然而，为了实现这一潜力，需要显着提高其效率。采用基于内皮细胞与载药磁性纳米载体双重功能化的集成细胞内药物抗再狭窄策略，为它们提供支架靶向递送的能力并增强抗再狭窄效果，后者是通过诱导和激活内皮一氧化氮合酶来实现的。雌二醇以其前体苯甲酸雌二醇 (E2Bz) 的形式配制在磁性纳米颗粒 (MNP) 中。将确定使用这种方法预防支架内再狭窄并在再现人类疾病关键特征的经过验证的动脉粥样硬化大鼠模型中实现促进再内皮化的可行性。将解决以下具体目标：目标 1：细胞内药物方法评估和将制定负载 E2Bz 的可生物降解 MNP 的优化，并对其尺寸、组成、磁性和药物释放特性进行表征。 MNP 的内化和降解动力学，以及 MNP 功能化内皮细胞 E2Bz 诱导的一氧化氮合成及其对共培养平滑肌细胞的生长抑制作用将是 Aim 1 实验的主要终点：AIM 2：靶向、将在大鼠中研究磁性靶向递送功能化细胞后的动脉定位、组织分布和内皮恢复。动脉粥样硬化/颈动脉支架模型。 再狭窄的程度将在分娩后两周通过计算机形态测定法确定，并且细胞功能化的药理作用将使用用负载空白 MNP 的细胞治疗的动物作为对照来描述。